The selective degradation of target proteins using small molecules is a new approach to the treatment of various diseases. Proteolysis Targeting Chimeric molecules (Protacs) are bifunctional molecules which can simultaneously bind a target protein and an E3 ubiquitin ligase thereby bringing the ligase and target in close proximity These bifunctional molecules allow the efficient ubiquitin transfer from the ligase complex to the target protein which is subsequently recognized by the proteasome and degraded. This degradation of the target protein provides treatment of diseases or conditions modulated through the target protein by effectively lowering the level of said target protein in the cells of the patient. An advantage of Protacsis that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of targeted proteins from virtually any class or family.
E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination and therefore are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. The development of ligands for E3 ligases has proven challenging. One suitable E3 ubiquitin ligase is the von Hippel-Lindau tumour suppressor (VHL), see for example WO2013/106643.
It would be desirable to identify further E3 ubiquitin ligase binding molecules to incorporate into Protac molecules.
Protacs employed to target proteins to the E3 ligase IAP (Inhibitors of Apoptosis) through the ligand bestatin have been proposed with limited success, see for example Ohoka et al, Cell Death and Disease, 2014, 5, e1513. Unfortunately bestatin is a non-specific ligand with multiple activities. IAP inhibitors are known which can be of use in their own right as antitumour agents, see for example L. Bai et al./Pharmacology & Therapeutics 144 (2014) 82-95 Apoptosis is one form of programmed cell-death and is a normal cellular process used by multi-cellular organisms to eliminate damaged or unwanted cells. Apoptosis is a tightly regulated process and faulty regulation of apoptosis is implicated in many human diseases, including cancer, autoimmune diseases, inflammation, and neurogenesis (Lowe S. W and Lin 2000 Carcinogenesis 21(3), 485-495, Nicholson D. W. 2000, Nature 407 (6805) 810-816, Reed J. C. 2002 Nat Rev Drug Discovery 1(2) 111-121).
Selective IAP inhibitors are disclosed, for example in WO 2014031487 WO 2014047024 which describe linked dimeric compounds. WO 2014055461 describes bivalent compounds and WO 2008128171, WO2008/016893, WO 2014/060768, WO2014/060767, and WO15092420 describe IAP inhibitors all with a view to treating disorders associated with apoptosis, particularly cancer.
The present inventors have identified E3 ligase IAP inhibitor compounds which when incorporated into Protacs as the “degradation component”, including Protacs targeting RIP2 Kinase, BTK and the estrogen receptor are capable of promoting target degradation.